GLYPHOSATE

Glyphosate is used to kill unwanted plants (weeds) in crop fields, amenity areas and home gardens, and on a global scale it has become the most widely used pesticide(1). The manufacturers of glyphosate-based herbicides claim their ‘low toxicity and environmental friendliness’(2). However, recent independent research indicates that glyphosate may not be as safe as previously thought.

What is glyphosate?
Glyphosate, sold most widely under the trade name Roundup, is applied as a herbicide both after the crop has germinated (post-emergent use) and before seeding (pre-emergent use in low-tillage cultivation). It acts non-selectively, killing a broad spectrum of plants including grasses, perennials and woody plants(3). Glyphosate is absorbed through the leaves and is then transported throughout the plant. It inhibits a metabolic pathway required to form essential amino acids that exist in plants and microorganisms but not in animals(4). Glyphosate is an organophosphonate or salt of a phosphonic acid. It does not inhibit activity of the enzyme acetylcholinesterase (as do organophosphates) that is crucial for transmission of nerve signals in animals and insects(5). 

Usage
Since its introduction during the mid-seventies, use of glyphosate has increased rapidly(6). In the USA in the years 1997 and 2002 it was among the five most used active ingredients, and second-most used by homeowners and the government or industry(7,8). The recent increase in use is largely due to the introduction of genetically modified (GM) glyphosate-tolerant crops, for example GM soybean in Argentina(9). Expansion in practice of low-tillage has also increased its use(10). Worldwide sales of glyphosate-based products exceeded US$3,000 million in 2002 and the main manufacturer Monsanto expects an increase in 2004 due to increased sales of their products (including ‘Roundup’) in Brazil(11,12).

Formulations of products based on glyphosate
Most glyphosate-based herbicides are formulated with one or more surfactants. The surfactant spreads the solution across the leaf, penetrates the leaf and enhances the uptake of glyphosate by the plant(13). A class of surfactants known as polyoxyethylene tallowamines (POEA) are used most frequently. These are mixtures of ethoxylated long-chain alkyl amines derived from fatty acids from animals(14) or tall oil (resin from pine wood)(15). Proportions of glyphosate and surfactant have not changed in many products over the last few years (manufacturers material safety data sheets)(16) and despite health concerns POEAs continue to be used, for example in ‘Roundup Ultra’(17). Other surfactants are also used, such as alcohol ethers and fatty acid esters18, or biodegradable rapeseed oil derivatives(19). Some glyphosate-based herbicide formulations contain a second active ingredient as several weeds have become resistant to glyphosate(20).

Acute toxicities of glyphosate-based herbicides
Acute toxicity refers to the immediate effects (0-7 days) of exposure to a substance. The US EPA ranks glyphosate in toxicity category III (these products bear the label: ‘Caution’)(21). However, some glyphosate formulations are in toxicity category I (‘Danger’) or II (‘Warning’) for primary eye irritation or skin irritation(22). Glyphosate is categorised by the World Health Organisation (WHO) in acute toxicity class U: ‘Product unlikely to present acute hazard in normal use’(23). Formulated products with a surfactant are either in WHO class U or in class III (‘Slightly Hazardous’)(24). Glyphosate was found to be irritating to the eyes and slightly irritating to the skin when tested on rabbits(25), while a Monsanto safety sheet says a formulation similar to ‘Roundup Original’ (41% glyphosate isopropylammonium salt, 8% surfactant and 51% water, by weight) caused severe eye irritation and destruction of eye tissue requiring more than 21 days to heal when tested on rabbits(26). Tests on rats revealed that formulations containing glyphosate and a POEA surfactant caused more severe respiratory effects and damage to lung tissue than glyphosate on its own(27), and POEA accounted for a major part of the toxicity of the product Roundup to different aquatic organisms(28).

Exposure of farm workers to smaller amounts of Roundup, for example by rubbing in an eye, is reported to have caused swelling of the eye and lid, rapid heartbeat and elevated blood pressure, or swelling of the face, due to residues transferred from the hands after touching leaky equipment, while accidental drenching caused eczema of the hands and arms which lasted two months(29). A safety evaluation concluded ‘that under present and expected conditions of use, Roundup does not pose a health risk to humans’(30). However, a case of acute toxic pneumonitis after inhalation of vapors and air-borne droplets containing glyphosate has been diagnosed, based on clinical evidence(31). In another case, inhalation of a mixture of glyphosate (isopropylamine salt) and the herbicide butafenacil (WHO class: not listed) led to high fever and general fatigue immediately afterwards(32). In 2002 in California, glyphosate accounted for systemic and respiratory health effects in four definite/probable and eight possible cases, and for effects involving only the eyes and/or skin in five definite/probable and two possible cases among agricultural workers(33). From 24 people in Denmark who were exposed to glyphosate by inhalation and from 42 exposed by topical contact, about three quarters developed poisoning symptoms, mostly related to the mouth, gastrointestinal tract and the airways(34). In the UK glyphosate has been the most frequent cause of complaints and poisoning incidents recorded in recent years by the Health and Safety Executive’s Pesticides Incidents Appraisal Panel (PIAP)(35). Aerial spraying of large areas in Colombia to eradicate cocoa and poppy crops has caused poisoning in over 4,000 people and very many animals in one area, and health impacts among over 35,000 indigenous people(36).

Prolonged exposure to glyphosate and chronic toxicity
Rats that had inhaled aerosols of one-third diluted ‘Roundup’ over several days showed irritations to the nose tissue, trachea and lungs(37). Relatively high dose of glyphosate applied to the skin of rabbits caused a slight degree of dermal irritation, while a much smaller amount of a formulated product caused skin irritation that required four weeks to heal(38). In rats and mice dietary exposure to glyphosate over three months caused lesions of the salivary glands(39).

In cultures of nerve cells previously exposed to the insecticide diazinon for two months, toxic effects of glyphosate appeared at a concentration several times lower than in non-exposed cells(40). The incidence of neurologic developmental effects increased more than threefold among children born to farmers in the US who used glyphosate(41). Roundup has been found to inhibit the production of steroid hormones and this may result in loss of fertility in men(42).

In tadpoles, glyphosate was seen to cause DNA damage(43). A study in the USA found that when farmers used several individual pesticides, including glyphosate, this was ‘associated with increased Non-Hodgin’s lymphoma (NHL) incidence’(44). NHL is a malignant tumor of lymphoid tissue, and a significant association in the incidence of NHL and exposure to glyphosate has been observed in Sweden(45). Studies on effects of different concentrations of glyphosate on chromosome aberrations and chromatid exchange in human and bovine white blood cells revealed ‘a dose-related increase in the percent of aberrant cells’(46), suggesting that ‘either oxidative stress or a mutagenic effect’(47) is induced.

Environmental fate and ecological impact of glyphosate
In formulated products POEAs were found to be more toxic than other surfactants and – when used according to label recommendations under normal use conditions – could be lethal to bluegill sunfish in very shallow water (less than 10 cm depth)(48). Exposure of tadpoles to low concentrations of glyphosate formulation for a short time revealed sublethal effects and led to significant mortality(49). Indirect effects of cereal herbicides including glyphosate are associated with the decline of 11 bird species in the UK(50).

Degradation of glyphosate in soil was found to be slow(51). A study in Denmark has found that: ‘glyphosate, when applied in late autumn, can leach through the root zone [1m below ground soil] at unacceptable concentrations in loamy soil’; average concentrations exceeded the European Drinking Water Standard (0.1 µg/l) at two sites for glyphosate, and at one for aminoethylphosphonic acid, a degradation product detected over one and a half years after application(52). The Danish government has proposed to restrict the use of glyphosate, preventing its use during the autumn and winter on clay soils where the risk of leaching is high within heavy rainfall. The restriction is due to come into force in 2004. 

Conclusion
It is often argued that glyphosate is an alternative to the use of herbicides with higher acute toxicities, such as 2,4-D or paraquat. However, there exists sufficient evidence that glyphosate can cause harmful chronic effects to health, and the Danish study on surface waters revealed an unforeseen way of behaviour in the environment. The use of glyphosate should be reduced substantially, especially in developing countries, to minimise acute and chronic effects on wildlife and human health.

This factsheet written by Richard Isenring is an update of a previous version: see PN 33, September 1996, p28-29.

References
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2. Franz JE, Mao MK, and Sikorski JA, Glyphosate: A unique global herbicide, ACS Monograph 189, American Chemical Society, Washington DC, US, 1997.
3. World Health Organisation, Food and Agriculture Organisation of the United Nations, Glyphosate, WHO/FAO Data Sheets on Pesticides No. 91, WHO/PCS/DS/96.91, July 1997 ( http://www.inchem.org/documents/pds/pds/pest91_e.htm).
4. Alibhai F and Stallings WC, Closing down on glyphosate inhibition – with a new structure for drug discovery, Proceedings of the National Academy of Science of the USA, 98(6) 2944-2946, 2001
5. WHO, FAO, op. cit. 3.
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18. Ibid.
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22. Ibid.
23. WHO, FAO, op. cit. 3.
24. WHO, FAO, op. cit. 3.
25. WHO, FAO, op. cit. 3.
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33. Department of Pesticide Regulation, Worker Health and Safety Branch, Illness and injuries related to pesticide exposure, PISP report 2002 (http://www.cdpr.ca.gov/docs/whs/pisp.htm).
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35. Pesticides Trust (now PAN UK), The price of resistance. The consequences of Roundup Ready soybeans, London 1997.
36. Williamson S, Aerial spraying devastates Colombian communities, Pesticides News, 53: 9, 2001.
37. WHO, FAO, op. cit. 3.
38. WHO, FAO, op. cit. 3.
39. WHO, FAO, op. cit. 3.
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42. Walsh LP, McCormick C, Martin C and Stocco DM, Roundup inhibits steroidogenesis by disrupting steroidogenic acute regulatory (StAR) protein expression, Environmental Health Perspectives, 108(8): 769-776, 2000.
43. Clements C, Ralph S and Petras M, Genotoxicity of selected herbicides in Rana catesbeiana tadpoles using the alkaline single-cell gel electrophoresis (comet) assay, Environmental and Molecular Mutagenesis, 29(3): 277-288, 1997.
44. De Roos AJ, Zahm SH, Cantor KP, Weisenburger DD, Holmes FF, Bumeister LF and Blair A, Integrative assessment of multiple pesticides as risk factors for non-Hodgkin’s lymphoma among men, Occupational and Environmental Medicine, 60(9): E11, 2003.
45. Hardell L, Eriksson M and Nordstrom M, Exposure to pesticides as risk factor for non-Hodgkin’s lymphoma and hairy cell leukaemia: pooled analysis of two Swedish case-control studies, Leukemia and Lymphoma, 43(5): 1043-1049, 2002.
46. Lioi MB, Scarfi MR, Santoro A, Barbieri R, Zeni O, Di Berardino D and Ursini MV, Genotoxicity and oxidative stress induced by pesticide exposure in bovine lymphocyte cultures in vitro, Mutation Research, 403(1-2): 13-20, 1998.
47. Lioi MB, Scarfi MR, Santoro A, Barbieri R, Zeni O, Di Berardino D and Ursini MV, Cytogenetic damage and induction of pro-oxidant state in human lymphocytes exposed in vitro to glyphosate, vinclozolin, atrazine, and DPX-E9636, Environmental Molecular Mutagenesis, 32(1): 39-46, 1998.
48. Haller WT and Stocker RK, Toxicity of 19 adjuvants to juvenile Lepomis macrochirus (bluegill sunfish), Environmental Toxicology and Chemistry, 22(3): 615-619, 2003.
49. Smith GR, Effects of acute exposure to a commercial formulation of glyphosate on the tadpoles of two species of anurans, Bulletin of Environmental Contamination and Toxicology, 67(4): 483-88, 2001.
50. Cambell LH and Cook AS, The indirect effects of pesticides on birds, Joint Nature Conservation Committee, Peterborough 1997.
51. Getenga ZM and Kengara FO, Mineralization of glyphosate in compost-amended soil under controlled conditions, Bulletin of Environmental Contamination and Toxicology, 72: 266-275, 2004.
52. Kjaer J (ed), The Danish Pesticide Leaching assessment Programme, Monitoring results May 1999 – June 2002, Summary of monitoring results, June 2003 (http://pesticidvarsling.dk/monitor_uk/2002_uk/index.html).

[This article first appeared in Pesticides News No. 64, June 2004, pages 20-21